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Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC

Besse, Benjamin, Charrier, Mélinda, Lapierre, Valérie, Dansin, Eric, Lantz, Olivier, Planchard, David, Le Chevalier, Thierry, Livartoski, Alain, Barlesi, Fabrice, Laplanche, Agnès, Ploix, Stéphanie, Vimond, Nadège, Peguillet, Isabelle, Théry, Clotilde, Lacroix, Ludovic, Zoernig, Inka, Dhodapkar, Kavita, Dhodapkar, Madhav, Viaud, Sophie, Soria, Jean-Charles, Reiners, Katrin S., Pogge von Strandmann, Elke, Vély, Frédéric, Rusakiewicz, Sylvie, Eggermont, Alexander, Pitt, Jonathan M., Zitvogel, Laurence, Chaput, Nathalie·2016·OncoImmunology
DOI 10.1080/2162402x.2015.1071008PMC PMC4839329
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Figure 1. Quality Control of IFN-γ-Dex vaccines. (A) Thirty-six batches of IFN-γ-Dex were produced and characterized by flow cytometry after capture on beads for surface expression of MHC-I, MHC-II, tetraspanins, CD40, CD80, CD86, CD54 and NKG2DL. MHC-II and total tetraspanin (CD63/81/82) expressions represented the key parameters for Dex definition and batch release (left panel) and were considered of potential therapeutic value when the ratio of MFI for MHC-II and tetraspanin compared with the isotype control mAb was > 5 (dotted line). Dex maturity is depicted in the pi-chart (right panel) summarizing the raw data of the middle panel indicating Dex MFI ratios for each parameter compared with its isotype control mAb. Dex were considered mature if the MFI ratio of CD40, CD80 and CD86 were all > 2 compared to isotype control staining, semi-mature if at least one of these markers was > 2, and immature when all three markers were < 2. (B) Spearman correlation between total protein content of Dex preparations and Dex MHC-II surface expression. Each dot represents one patient preparation. (C) Validation of MART-1 peptide presentation on Dex surface: HLA-A2+ Dex were pre-incubated (or not) with HLA-A2 negative DCs prior to incubation with the HLA-A2-restricted, MART-1-specific LT11 clone. IFN-γ levels were determined by commercial ELISA from the 48h-culture supernatants. Each dot represents a mean of duplicate wells for individual patient Dex preparations. A paired t-test of the antigenicity of Dex alone versus Dex pulsed onto DC indicates significant results at p < 0.05.
Figure 1. Quality Control of IFN-γ-Dex vaccines. (A) Thirty-six batches of IFN-γ-Dex were produced and characterized by flow cytometry after capture on beads for surface expression of MHC-I, MHC-II, tetraspanins, CD40, CD80, CD86, CD54 and NKG2DL. MHC-II and total tetraspanin (CD63/81/82) expressions represented the key parameters for Dex definition and batch release (left panel) and were considered of potential therapeutic value when the ratio of MFI for MHC-II and tetraspanin compared with the isotype control mAb was > 5 (dotted line). Dex maturity is depicted in the pi-chart (right panel) summarizing the raw data of the middle panel indicating Dex MFI ratios for each parameter compared with its isotype control mAb. Dex were considered mature if the MFI ratio of CD40, CD80 and CD86 were all > 2 compared to isotype control staining, semi-mature if at least one of these markers was > 2, and immature when all three markers were < 2. (B) Spearman correlation between total protein content of Dex preparations and Dex MHC-II surface expression. Each dot represents one patient preparation. (C) Validation of MART-1 peptide presentation on Dex surface: HLA-A2+ Dex were pre-incubated (or not) with HLA-A2 negative DCs prior to incubation with the HLA-A2-restricted, MART-1-specific LT11 clone. IFN-γ levels were determined by commercial ELISA from the 48h-culture supernatants. Each dot represents a mean of duplicate wells for individual patient Dex preparations. A paired t-test of the antigenicity of Dex alone versus Dex pulsed onto DC indicates significant results at p < 0.05.CC BY-NC · PubMed Central
Figure 2. Clinical responses to Dex vaccination post-chemotherapy. Progression free survival (A), and OS (B) of the cohort of 22 patients recruited into the trial (95% confidence interval). (C–E) Case report of patient 037. Thoracic (C) and brain (D) CT scans as well as a longitudinal follow up by MRI of the 11th dorsal vertebra (E) are shown for the best clinical response obtained in one patient with a stage IV NSCLC. Imaging at baseline (before-chemotherapy), post-chemotherapy (before commencement of Dex injections), at 3 mo after the first Dex injections, and at the last Dex injection before surgery of the thoracic lesion.
Figure 2. Clinical responses to Dex vaccination post-chemotherapy. Progression free survival (A), and OS (B) of the cohort of 22 patients recruited into the trial (95% confidence interval). (C–E) Case report of patient 037. Thoracic (C) and brain (D) CT scans as well as a longitudinal follow up by MRI of the 11th dorsal vertebra (E) are shown for the best clinical response obtained in one patient with a stage IV NSCLC. Imaging at baseline (before-chemotherapy), post-chemotherapy (before commencement of Dex injections), at 3 mo after the first Dex injections, and at the last Dex injection before surgery of the thoracic lesion.CC BY-NC · PubMed Central
Figure 3. IFN-γ-Dex-mediated induction of NKp30 effector functions and correlation with progression-free survival. (A) NSCLC patients exhibit markedly reduced NKp30 expression on circulating NK cells. Flow cytometry determinations of expression levels of NK receptors (NKG2D, NKp30 and CD16) in the peripheral whole blood CD3−CD56+ NK cells of HV and NSCLC patients at their inclusion into the trial (baseline, T0). (B) Flow cytometry analyses were performed after freezing/thawing, at T0 and post 4 Dex injections (T2). (C) Flow cytometry analyses of NK cell functions after cross-linking of NKp30 as measured by CD107a upregulation and cytokine intracellular staining (at 5 h), comparing baseline (T0) and post 4 IFN-γ-Dex vaccinations (T2). (D) IFN-γ-Dex-mediated NKp30 triggering is associated with prolonged PFS. NSCLC patients were segregated into two groups according to the median PFS of the whole cohorts (< 2.2 mo, and > 2.2 mo respectively). CD107a upregulation and cytokine production following NKp30 cross-linking are shown at T0 and T2 for each subgroup. Patient #037, who experienced a long-term stabilization post Dex therapy as shown in Figure 2 is indicated with red dots. The experiment was performed in triplicate wells, the three wells were pooled before FACS staining. Each dot represents one patient. Paired t-test p-value is indicated on the graph.
Figure 3. IFN-γ-Dex-mediated induction of NKp30 effector functions and correlation with progression-free survival. (A) NSCLC patients exhibit markedly reduced NKp30 expression on circulating NK cells. Flow cytometry determinations of expression levels of NK receptors (NKG2D, NKp30 and CD16) in the peripheral whole blood CD3−CD56+ NK cells of HV and NSCLC patients at their inclusion into the trial (baseline, T0). (B) Flow cytometry analyses were performed after freezing/thawing, at T0 and post 4 Dex injections (T2). (C) Flow cytometry analyses of NK cell functions after cross-linking of NKp30 as measured by CD107a upregulation and cytokine intracellular staining (at 5 h), comparing baseline (T0) and post 4 IFN-γ-Dex vaccinations (T2). (D) IFN-γ-Dex-mediated NKp30 triggering is associated with prolonged PFS. NSCLC patients were segregated into two groups according to the median PFS of the whole cohorts (< 2.2 mo, and > 2.2 mo respectively). CD107a upregulation and cytokine production following NKp30 cross-linking are shown at T0 and T2 for each subgroup. Patient #037, who experienced a long-term stabilization post Dex therapy as shown in Figure 2 is indicated with red dots. The experiment was performed in triplicate wells, the three wells were pooled before FACS staining. Each dot represents one patient. Paired t-test p-value is indicated on the graph.CC BY-NC · PubMed Central
Figure 4. Dex MHC-II molecules predict BAG6 / NKp30-mediated NK cell activity. (A) Dex preparations produced for the whole cohort of NSCLC patients were divided into two groups either side of the median MHC-II quantity of 2.18 × 1013 molecules (< 2.18 × 1013 MHC-II, and > 2.18 × 1013 MHC-II respectively), and CD107a upregulation and cytokine production following NKp30 cross-linking were determined comparing baseline (T0) and post 4 IFN-γ-Dex vaccinations (T2). The experiment was performed in triplicate wells, with the three wells pooled before FACS staining. Patient #037 with long-term stabilization post-Dex therapy as shown in Fig. 2 is indicated with red dots. Paired t-test p-value is indicated on the graph. (B) Spearman correlations between IFN-γ levels (measured on Dex batches) and MHC-II quantity within the same preparations. (C) Spearman correlations between BAG6 quantity (measured by ELISA on Dex batches) and MHC-II quantity in the same Dex.
Figure 4. Dex MHC-II molecules predict BAG6 / NKp30-mediated NK cell activity. (A) Dex preparations produced for the whole cohort of NSCLC patients were divided into two groups either side of the median MHC-II quantity of 2.18 × 1013 molecules (< 2.18 × 1013 MHC-II, and > 2.18 × 1013 MHC-II respectively), and CD107a upregulation and cytokine production following NKp30 cross-linking were determined comparing baseline (T0) and post 4 IFN-γ-Dex vaccinations (T2). The experiment was performed in triplicate wells, with the three wells pooled before FACS staining. Patient #037 with long-term stabilization post-Dex therapy as shown in Fig. 2 is indicated with red dots. Paired t-test p-value is indicated on the graph. (B) Spearman correlations between IFN-γ levels (measured on Dex batches) and MHC-II quantity within the same preparations. (C) Spearman correlations between BAG6 quantity (measured by ELISA on Dex batches) and MHC-II quantity in the same Dex.CC BY-NC · PubMed Central
Figure 5. Circulating sBAG6 and NKp30 anergy restored by IFN-γ-Dex. (A) Monitoring of serum soluble BAG6 or soluble B7-H6 at diagnosis and T2 in NSCLC patients by ELISA expressed as percentages of positive samples (cut-off values, 0.5 ng/mL for BAG6; 0.6 ng/mL for sB7-H6) (left panel) and genuine values (right panel). (B–C) Idem as in Fig. 3 monitoring NKp30- (B) or CD16- (C) mediated effector functions in the subsets of patients presenting or not presenting detectable sBAG6 at diagnosis (T0) and (T2). Eleven patients were assessed and the means±SEM of flow cytometry values are shown. Paired t-test p-value is indicated on the graph.*p<0.05.
Figure 5. Circulating sBAG6 and NKp30 anergy restored by IFN-γ-Dex. (A) Monitoring of serum soluble BAG6 or soluble B7-H6 at diagnosis and T2 in NSCLC patients by ELISA expressed as percentages of positive samples (cut-off values, 0.5 ng/mL for BAG6; 0.6 ng/mL for sB7-H6) (left panel) and genuine values (right panel). (B–C) Idem as in Fig. 3 monitoring NKp30- (B) or CD16- (C) mediated effector functions in the subsets of patients presenting or not presenting detectable sBAG6 at diagnosis (T0) and (T2). Eleven patients were assessed and the means±SEM of flow cytometry values are shown. Paired t-test p-value is indicated on the graph.*p<0.05.CC BY-NC · PubMed Central

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Authors
Besse, B., Charrier, M., Lapierre, V., Dansin, E., Lantz, O., Planchard, D., Le Chevalier, T., Livartoski, A., Barlesi, F., Laplanche, A., Ploix, S., Vimond, N., Peguillet, I., Théry, C., Lacroix, L., Zoernig, I., Dhodapkar, K., Dhodapkar, M., Viaud, S., Soria, J.-C., Reiners, K. S., Pogge von Strandmann, E., Vély, F., Rusakiewicz, S., Eggermont, A., Pitt, J. M., Zitvogel, L., & Chaput, N.
Venue
OncoImmunology
Publisher
Informa UK Limited
Published
2016-04-02
Volume
5
Issue
4
ISSN
2162-402X
DOI
10.1080/2162402x.2015.1071008
PMC
PMC4839329
Cited by
749
References
3
Language
en
Licence
creativecommons.org/licenses/by-nc/3.0/ (vor)

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